Systems and Methods for Predicitng Ligand-Protein Binding Interactions

Abstract

The present invention relates to systems and methods for determining a candidate molecule's ability to bind a target protein comprising calculating a score for the candidate molecule, wherein the score is a function of a position of the candidate molecule relative to a field of distribution densities on a three-dimensional target protein structure. The systems and methods are useful for designing active molecules in drug discovery. Methods of this invention can be implemented in a computer system and may be embodied as computer code in a computer readable medium.

1 . A method for determining a candidate molecule's ability to bind a target protein, comprising calculating a score for the candidate molecule, wherein the score is a function of a position of the candidate molecule relative to a field of distribution densities on a three-dimensional target protein structure. 
   
   
       2 . The method of  claim 1 , wherein the score is calculated according to the following equation: 
     
       
         
           
             Score 
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 C 
                 * 
                 
                   
                     Q 
                     i 
                   
                   Q 
                 
               
             
           
         
       
     
     wherein Q i  is a distribution density factor or any other measure of occurrence frequency of the atom type at its location or at the location of the nearest grid point in the binding site; Q is the optimal distribution density factor or any other measure of occurrence frequency for the atom type; C is the proportionality constant for the atom type; and n is the number of atoms in the candidate molecule. 
   
   
       3 . The method of  claim 1 , further comprising the step of comparing the score of the candidate molecule to a score threshold value. 
   
   
       4 . A method for determining a candidate molecule's ability to bind a target protein, comprising optimizing a score according to a position of the candidate molecule relative to a field of distribution densities of the target protein structure. 
   
   
       5 . The method of  claim 4 , further comprising the step of comparing the optimized score to a score threshold value. 
   
   
       6 . The method of  claim 4 , wherein the step of optimizing the score comprises the steps of:
 a) obtaining three-dimensional coordinates for each atom in the candidate molecule;   b) determining a set of translational and rotational geometric parameters for an initial placement of the candidate molecule in the target protein binding site structure;   c) determining a new set of translational and rotational geometric parameters site, wherein the new set of translational and rotational geometric parameters is determined by maximizing the overlap between atom positions of the candidate molecule and the field of distribution densities; and   d) evaluating the candidate molecule-target protein complex geometry.   
   
   
       7 . The method of  claim 6 , wherein the step of determining a set of translational and rotational geometric parameters for an initial placement of the candidate molecule in the target protein binding site structure is accomplished with a set of randomly selected translational and rotational parameters. 
   
   
       8 . The method of  claim 6 , wherein the step of determining a set of translational and rotational geometric parameters for an initial placement of the candidate molecule in the target protein binding site structure is accomplished with a set of specifically selected translational and rotational parameters. 
   
   
       9 . The method of  claim 6 , wherein the step of determining a set of translational and rotational geometric parameters for an initial placement of the candidate molecule in the target protein binding site structure comprises the steps of:
 a) selecting n atoms in the candidate molecule;   b) selecting n specific locations in the target protein binding site; and   c) aligning the atoms in the candidate molecule with the corresponding locations in the target protein binding site by rotational and translational movement to minimize the following equation:   
     
       
         
           
             
               I 
                
               
                 ( 
                 
                   T 
                   , 
                   R 
                 
                 ) 
               
             
             = 
             
               
                 ∑ 
                 
                   j 
                   = 
                   1 
                 
                 n 
               
                
               
                  
                 
                   Mj 
                   - 
                   Aj 
                 
                  
               
             
           
         
       
     
     wherein T is a translation vector; R is a rotation 3×3 matrix; n is the number of selected atoms in the candidate molecule; Mj is a vector defining a position of the distribution density maximum j; and Aj is a vector defining the position of the corresponding atom j in the candidate molecule. 
   
   
       10 . The method of  claim 6 , wherein the step of determining the new set of translational and rotational geometric parameters comprises the steps of:
 a) determining distribution density factors Q i  for locations of atoms i in docked molecule; and   b) calculating a position of the candidate molecule in the target protein binding site I(T,R,B).   
   
   
       11 . The method of  claim 10 , wherein the position of the candidate molecule in the target protein binding site is calculated according to the following equation: 
     
       
         
           
             
               I 
               
                 ( 
                 
                   T 
                   , 
                   R 
                   , 
                   B 
                 
                 ) 
               
             
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 CQ 
                 i 
               
             
           
         
       
     
     wherein n is the number of atoms in the candidate molecule; Q i  is the distribution density factor at location of the i th  atom in a candidate molecule; I(T,R,B) represents the position of the candidate molecule in the binding site given by translational (T), rotational (R), and rotatable bond parameters (B); and C is the proportionality constant for the atom type. 
   
   
       12 . The method of  claim 10 , wherein the position of the candidate molecule in the target protein binding site is calculated according to the following equation: 
     
       
         
           
             
               I 
               
                 ( 
                 
                   T 
                   , 
                   R 
                   , 
                   B 
                 
                 ) 
               
             
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 
                   CQ 
                   i 
                 
                  
                 
                   F 
                   i 
                 
               
             
           
         
       
     
     wherein n is the number of atoms in the candidate molecule; Q i  is the distribution density factor at location of the i th  atom in a candidate molecule; I(T,R,B) represents the position of the candidate molecule in the binding site given by translational (T), rotational (R), and rotatable bond parameters (B); C is the proportionality constant for the atom type; and F i  represents the proportion of atom's surface proportion in the contact with the protein surface. 
   
   
       13 . The method of  claim 10 , wherein the position of the candidate molecule in the target protein binding site is calculated according to the following equation: 
     
       
         
           
             
               I 
               
                 ( 
                 
                   T 
                   , 
                   R 
                   , 
                   B 
                 
                 ) 
               
             
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 CD 
                 i 
               
             
           
         
       
     
     wherein n is the number of atoms in the candidate molecule; D i  is the distance between i th  atom in the candidate molecule and a respective local distribution density maximum maximum; I(T,R,B) represents the position of a ligand in a binding site given by translational (T), rotational (R), and rotatable bond parameters (B); and C is the proportionality constant for the atom type. 
   
   
       14 . The method of  claim 10 , wherein the position of the candidate molecule in the target protein binding site is calculated according to the following equation: 
     
       
         
           
             
               I 
               
                 ( 
                 
                   T 
                   , 
                   R 
                   , 
                   B 
                 
                 ) 
               
             
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 
                   CD 
                   i 
                 
                  
                 
                   F 
                   i 
                 
               
             
           
         
       
     
     wherein n is the number of atoms in the candidate molecule; D i  is the distance between i th  atom in the candidate molecule and a respective local distribution density maximum maximum; I(T,R,B) represents the position of a ligand in a binding site given by translational (T), rotational (R), and rotatable bond parameters (B); C is the proportionality constant for the atom type; and F i  represents the proportion of atom's surface proportion in the contact with the protein surface. 
   
   
       15 . The method of  claim 6 , further comprising the step of repeating steps b) and c) until the overlap between atom positions of the candidate molecule and the field of distribution densities is maximized. 
   
   
       16 . The method of  claim 6 , wherein the step of evaluating the candidate molecule-target protein complex geometry comprises calculating a score according to the following equation: 
     
       
         
           
             Score 
             = 
             
               
                 ∑ 
                 
                   i 
                   = 
                   1 
                 
                 n 
               
                
               
                 C 
                 * 
                 
                   
                     Q 
                     i 
                   
                   Q 
                 
               
             
           
         
       
     
     wherein Q i  is a distribution density factor or any other measure of occurrence frequency of the atom type at its location or at the location of the nearest grid point in the binding site; Q is the optimal distribution density factor or any other measure of occurrence frequency for the atom type; C is the proportionality constant for the atom type; and n is the number of atoms in the candidate molecule. 
   
   
       17 . The method of  claims 1  or  4 , wherein the target protein is selected from the group consisting of Raf kinase, Rho kinase, N{tilde over (F)}□B, VEGF receptor kinase, JAK-3, CDK2, FLT-3, EGFR kinase, PKA, p21-activated kinase, MAPK, JNK, AMPK, phosphodiesterase PDE4, Abl kinase, phosphodiesterase PDE5, ADAM33, HIV-1 protease, HIV integrase, RSV integrase, XIAP, thrombin, tissue type plasminogen activator, matrix metalloproteinase, beta secretase, src kinase, fyn kinase, lyn kinase, ZAP-70 kinase, ERK-1, p38 MAPK, CDK4, CDK5, GSK-3, KIT kinase, FLT-1, FLT-4, KDR kinase, and COT kinase. 
   
   
       18 . A system for discovering a molecule with a binding affinity toward a protein target comprising: a processor; and a memory in electrical communication with the processor, wherein the processor is configured to carry out the method of  claim 1 . 
   
   
       19 . A computer readable medium having computer readable program code embodied therein, wherein the computer readable program code causes the computer to carry out the method of  claim 2 . 
   
   
       20 . A computer system comprising: a processor and a memory in electrical communication with the processor, wherein the memory has stored therein data indicative of a three-dimensional target protein binding site representation, comprising the binding site data set produced according to the method of  claim 4 . 
   
   
       21 . A computer program product comprising a computer usable medium having computer readable program code comprising computer instructions to carry out the method of  claim 6 . 
   
   
       22 . A method executed by a computer under the control of a program, said computer including a memory for storing said program, said method comprising the steps of the method of  claim 9 . 
   
   
       23 . A computer implemented method for modeling a target protein binding site for determining a candidate molecule's ability to binding to the target protein binding site, comprising the steps of the method of  claim 14 .